We study the transmissible spongiform encephalopathies (TSEs or prion disease), which are fatal neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy and chronic wasting disease (CWD). Our goal is to gain a better understanding of the underlying mechansims of TSE diseases in order to develop effective treatments. A key focus of these efforts is to understand the conversion of normal PrP (PrP-sen) to PrP-res, the abnormal form of prion protein (PrP) that appears to underlie TSE transmission and pathogenesis. A number of different cell biological, biochemical, biophysical and in vivo experimental approaches have been employed. [unreadable] [unreadable] During FY2007 we have 1) developed ultrasensitive and relatively rapid prion assays based on prion-seeded conversion of cell-free conversion of full-length recombinant PrP, 2) determined structure-activity relationships of cyclic tetrapyrroles as potent PrP-res inhibitors and anti-TSE drugs, 3) continued to characterize the adaptation of chronic wasting disease from deer and elk to hamsters and transgenic mice expressing hamster PrP-sen, 4) purified and analyzed strain-dependent ultrastructures of amyloid fibrils from scrapie-infected GPI anchorless PrP transgenic mice, 5) showed that the natural cyclic tetrapyrrole, hemin, binds to normal PrP and causes it to aggregate and be endocytosed from the surface of cells, and 6) developed an new potentially high-throughput fluroescence polarization assay for anti-TSE compounds.